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OBJECTIVE: To test the hypothesis that some antiphospholipid antibodies (aPL) in patients with the antiphospholipid syndrome (APS) recognize a conformational epitope shared by beta(2)-glycoprotein I (beta(2)GPI; the major autoantigen for the antiphospholipid antibodies) and the homologous catalytic domains of several serine proteases (such as thrombin, activated protein C [APC], and plasmin) involved in hemostasis. METHODS: We generated 4 new IgG monoclonal aPL (2 screened against beta(2)GPI, 1 against thrombin, and 1 against protein C) from 2 APS patients. The monoclonal antibodies (mAb) were analyzed for binding to beta(2)GPI, thrombin, APC, and plasmin, as well as for anticardiolipin antibody (aCL) activity. To demonstrate a shared epitope between beta(2)GPI and a serine protease, 1 mAb was studied by cross-inhibition analysis. RESULTS: Both of the IgG anti-beta(2)GPI mAb bound to thrombin, APC, and plasmin. On the other hand, the 1 anti-thrombin mAb and the 1 anti-protein C mAb also bound to beta(2)GPI. Moreover, the binding of 1 cross-reactive mAb to beta(2)GPI was inhibited by alpha-thrombin (which contains only the catalytic domain of thrombin). All 4 mAb displayed aCL activity. CONCLUSION: Taken together with the findings that some aCL bind to several serine proteases that participate in hemostasis and share homologous catalytic domains, these data demonstrate that some aCL in APS patients recognize one or more conformational epitopes shared by beta(2)GPI and the catalytic domains of disease-relevant serine proteases. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with rheumatoid arthritis (RA) provide an important opportunity for understanding care of patients with a serious chronic condition. OBJECTIVES: We sought to characterize the complexity of care for patients with RA, including metrics describing the patient, the disease, and use of the health care system across time and place. METHODS: We undertook a prospective cohort study of 568 community-dwelling patients with RA by using observational data from clinically detailed telephone interviews at baseline and 2 years later in addition to medical record abstraction. Health status, comorbidity, use of disease-modifying antirheumatic drugs, visits, providers, provider types, encounter settings, and the discontinuity between patients and providers were studied. RESULTS: Within a 12-month window, 568 patients had 8686 outpatient encounters with the health care system with a mean of 3.41 unique providers per patient associated with a mean of 5 primary care and 6 rheumatologist visits. Half did not see a primary care physician, and 20% did not see a rheumatologist during 6-month periods despite their use of potentially toxic drugs, a mean of 4 comorbidities and progressive RA. Over the course of 24 months, 29% of patients changed their primary care provider, and 15% changed their rheumatologist. Patients were moderately impaired with mean SF-12 physical component score 37 (SD, 9). CONCLUSION: Patients with RA have frequent encounters with multiple providers and also frequent discontinuity of care. Recognizing the complexity of the care of patients with a chronic disease across multiple dimensions provides an opportunity to better understand challenges and opportunities in delivering high quality care. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To study 5 type I interferon (IFN)-inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) in patients with systemic lupus erythematosus (SLE) and to correlate expression levels with disease activity and/or clinical manifestations. METHODS: Peripheral blood cells were obtained from 48 SLE patients, 48 normal controls, and 22 rheumatic disease controls, and total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real-time polymerase chain reaction, standardized to a housekeeping gene, and summed to an IFN score. Disease activity was determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) composite. RESULTS: Each gene was highly expressed in SLE patients compared with normal controls (P

OBJECTIVE: Women with systemic lupus erythematosus (SLE) have a 7-50-fold increased risk of coronary artery disease (CAD). In the general population, oxidized low-density lipoprotein (ox-LDL) increases the risk for CAD. Normal high-density lipoproteins (HDLs) protect LDL from oxidation; proinflammatory HDLs do not. This study was undertaken to determine whether patients with SLE, who have chronic inflammation that causes oxidative damage, have more proinflammatory HDL and higher levels of ox-LDL, thus predisposing them to atherosclerosis. METHODS: One hundred fifty-four women with SLE, 48 women with rheumatoid arthritis (RA), and 72 healthy controls were studied. The ability of the patients' HDL to prevent oxidation of normal LDL was measured. Values >1.0 (the value assigned for LDL oxidation in the absence of HDL) after the addition of HDL indicated proinflammatory HDL. Plasma ox-LDL levels were measured as the amount of oxidation produced by the patient's LDL after the removal of HDL. RESULTS: SLE patients had more proinflammatory HDL (mean +/- SD score 1.02 +/- 0.57, versus 0.68 +/- 0.28 in controls [P < 0.0001] and 0.81 +/- 0.22 in RA patients [P = 0.001 versus SLE patients]). A higher proportion of SLE patients had proinflammatory HDL: 44.7% of SLE patients versus 4.1% of controls and 20.1% of RA patients had scores >1.0 (P < 0.006 between all groups). Levels of ox-LDL correlated with levels of proinflammatory HDL (r = 0.37, P < 0.001). SLE patients with CAD had significantly higher proinflammatory HDL scores than patients without CAD (P < 0.001). CONCLUSION: HDLs are proinflammatory in a significant proportion of SLE patients and are associated with elevated levels of ox-LDL. Abnormal HDLs impair the ability to prevent LDL oxidation and may predispose to atherosclerosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To test the hypotheses that some plasmin-reactive anticardiolipin antibodies (aCL) may bind to tissue plasminogen activator (tPA) and that some of the tPA-reactive aCL may inhibit tPA activity. METHODS: We studied the reactivity of 8 patient-derived monoclonal aCL with tPA and examined the presence of IgG anti-tPA antibodies in patients with the antiphospholipid syndrome (APS). The effects of the reactive monoclonal aCL on the activity of tPA were also examined. RESULTS: Six patient-derived plasmin-reactive monoclonal aCL bound to tPA. Analysis of plasma samples revealed that 10 of 80 APS patients (12.5%) and 1 of 81 systemic lupus erythematosus patients (1.2%) had antibodies against fibrin-associated tPA, based on a cutoff value equal to the mean + 2SD of the level in 28 normal subjects. Of the 6 tPA-reactive monoclonal aCL, 2 of them (CL1 and CL15) inhibited tPA activity. CONCLUSION: Some of the plasmin-reactive aCL in APS patients may bind to tPA. Of the tPA-reactive aCL, some (such as CL1 and CL15) may inhibit tPA activity and, thus, may be prothrombotic in the host. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Recent case-control studies show associations of the minor T allele (of the C1858T single-nucleotide polymorphism corresponding to the R620W amino acid substitution) of PTPN22 with multiple autoimmune diseases, including systemic lupus erythematosus (SLE). We performed family-based association studies of this polymorphism in 4 independent cohorts containing SLE patients and their parents and/or other family members. METHODS: A total of 2,689 individuals from 902 independent Caucasian families with SLE were genotyped using polymerase chain reaction pyrosequencing (cohorts 1 and 2) and the Sequenom MassArray system (cohorts 3 and 4). The transmission disequilibrium test (TDT) and the pedigree disequilibrium test (PDT) were conducted to assess the evidence of association. RESULTS: The 1858 C > T allele frequencies of the parents showed no deviation from Hardy-Weinberg equilibrium within each cohort. No evidence of preferential transmission of the T allele from heterozygous parents to their affected offspring was observed in each of the 4 cohorts or in the combined sample. Consistent with the TDT result, the PDT analysis revealed no significant association between the T allele and SLE. In 54 of the 661 SLE patients (cohorts 1 and 3) with documented autoimmune thyroid disease, the T allele frequency was higher than in individuals with SLE alone (16.7% versus 8.5%; P = 0.008, odds ratio 2.16 [95% confidence interval 1.25-3.72]). CONCLUSION: The R620W polymorphism of the PTPN22 gene is not a major risk allele for SLE susceptibility in our sample of Caucasian individuals from northern America, the UK, or Finland, but it appears to be a risk factor for the concurrent autoimmune diseases of autoimmune thyroid disease and SLE. [ABSTRACT FROM AUTHOR]

Background: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE).Objective: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE.Design: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002.Setting: 16 university-affiliated rheumatology clinics or practices in 11 U.S. states.Patients: 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE.Interventions: 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group.Measurements: The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite.Results: Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis.Limitations: Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis.Conclusions: Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo. [ABSTRACT FROM AUTHOR]

The V-regions of anti-DNA antibodies contain determinants which can drive the autoimmune in SLE. Most of the evidence comes from murine studies where VH-derived epitopes accelerate the disease process in lupus prone-mice and can elicit mild inflammatory changes reminiscent of lupus in healthy animals. T helper cells reactive with VH peptides arise spontaneously during the disease and are thought to assist production of both anti-peptide antibodies and the generation of autoantibodies that deposit in the glomeruli. In mice stimulatory epitopes may be unique to autoantibodies. As tolerogens VH peptides may delay or diminish the autoimmune response by altering the production of cytokines. An artificial VH peptide, (pCONCENSUS) has been derived and this inhibits responses to VH and other autoantigens but leaves the murine immune system intact and able to generate reponses to external antigens. Limited number of studies of V-region determinants of human anti-DNA MAbs indicate prior sensitization of lupus T cells to VH determinants and that V-region reactive T cells are not deleted in periphery of healthy individuals. [ABSTRACT FROM AUTHOR]

Genes encoded within organelle genomes often evolve at rates different from those in the nuclear genome. Here, we analyzed the relative rates of nucleotide substitution in the mitochondrial, apicoplast and nuclear genomes in four different lineages of Plasmodium species (malaria parasites) infecting mammals. The rates of substitution in the three genomes exhibit substantial variation among lineages, with the relative rates of nuclear and mitochondrial DNA being particularly divergent between the Laverania (including Plasmodium falciparum) and Vivax lineages (including Plasmodium vivax). Consideration of synonymous and nonsynonymous substitution rates suggests that their variation is largely due to changes in mutation rates, with constraints on amino acid replacements remaining more similar among lineages. Mitochondrial DNA mutation rate variations among lineages may reflect differences in the long-term average lengths of the sexual and asexual stages of the life cycle. These rate variations have far-reaching implications for the use of molecular clocks to date Plasmodium evolution., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

HIV-1 envelope glycoprotein (Env) conformation substantially impacts antibody-dependent cellular cytotoxicity (ADCC). Envs from primary HIV-1 isolates adopt a prefusion "closed" conformation, which is targeted by broadly neutralizing antibodies (bnAbs). CD4 binding drives Env into more "open" conformations, which are recognized by non-neutralizing Abs (nnAbs). To better understand Env-Ab and Env-CD4 interaction in CD4+ T cells infected with HIV-1, we simultaneously measured antibody binding and HIV-1 mRNA expression using multiparametric flow cytometry and RNA flow fluorescent in situ hybridization (FISH) techniques. We observed that env mRNA is almost exclusively expressed by HIV-1 productively infected cells that already downmodulated CD4. This suggests that CD4 downmodulation precedes env mRNA expression. Consequently, productively infected cells express "closed" Envs on their surface, which renders them resistant to nnAbs. Cells recognized by nnAbs were all env mRNA negative, indicating Ab binding through shed gp120 or virions attached to their surface. Consistent with these findings, treatment of HIV-1-infected humanized mice with the ADCC-mediating nnAb A32 failed to lower viral replication or reduce the size of the viral reservoir. These findings confirm the resistance of productively infected CD4+ T cells to nnAbs-mediated ADCC and question the rationale of immunotherapy approaches using this strategy., Importance: Antibody-dependent cellular cytotoxicity (ADCC) represents an effective immune response for clearing virally infected cells, making ADCC-mediating antibodies promising therapeutic candidates for HIV-1 cure strategies. Broadly neutralizing antibodies (bNAbs) target epitopes present on the native "closed" envelope glycoprotein (Env), while non-neutralizing antibodies (nnAbs) recognize epitopes exposed upon Env-CD4 interaction. Here, we provide evidence that env mRNA is predominantly expressed by productively infected cells that have already downmodulated cell-surface CD4. This indicates that CD4 downmodulation by HIV-1 precedes Env expression, making productively infected cells resistant to ADCC mediated by nnAbs but sensitive to those mediated by bnAbs. These findings offer critical insights for the development of immunotherapy-based strategies aimed at targeting and eliminating productively infected cells in people living with HIV., Competing Interests: The authors declare no conflict of interest.

The majority of naturally elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs) because they are unable to recognize the Env trimer in its native "closed" conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) provided that Env is present on the cell surface in its "open" conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer. HIV-1 limits this vulnerability by downregulating CD4 from the surface of infected cells, thus preventing a premature encounter of Env with CD4. Small CD4-mimetics (CD4mc) sensitize HIV-1-infected cells to ADCC by opening the Env glycoprotein and exposing CD4-induced (CD4i) epitopes. There are two families of CD4i nnAbs, termed anti-cluster A and anti-CoRBS Abs, which are known to mediate ADCC in the presence of CD4mc. Here, we performed Fab competition experiments and found that anti-gp41 cluster I antibodies comprise a major fraction of the plasma ADCC activity in people living with HIV (PLWH). Moreover, addition of gp41 cluster I antibodies to cluster A and CoRBS antibodies greatly enhanced ADCC-mediated cell killing in the presence of a potent indoline CD4mc, CJF-III-288. This cocktail outperformed broadly neutralizing antibodies and even showed activity against HIV-1-infected monocyte-derived macrophages. Thus, combining CD4i antibodies with different specificities achieves maximal ADCC activity, which may be of utility in HIV cure strategies.IMPORTANCEThe elimination of HIV-1-infected cells remains an important medical goal. Although current antiretroviral therapy decreases viral loads below detection levels, it does not eliminate latently infected cells that form the viral reservoir. Here, we developed a cocktail of non-neutralizing antibodies targeting highly conserved Env regions and combined it with a potent indoline CD4mc. This combination exhibited potent ADCC activity against HIV-1-infected primary CD4 + T cells as well as monocyte-derived macrophages, suggesting its potential utility in decreasing the size of the viral reservoir., Competing Interests: The authors declare no conflict of interest.

Sooty mangabeys (SMs) are natural hosts of simian immunodeficiency virus (SIV) and do not progress to AIDS despite high viral replication. The main factors involved in the benign nature of this infection are (i) low level of immune activation, (ii) relative preservation of specific CD4+ T-cell subsets from direct virus infection, and (iii) absence of microbial translocation from the gut to the systemic circulation. To determine the impact of SIV infection on underlying cause of death, we retrospectively analyzed data from 307 SMs (219 SIV infected and 88 uninfected) housed at the Emory Primate Center that have died between 1986 and 2022. Interestingly, we found that SIV-infected SMs live ~4 years longer than SIV-uninfected SMs, although this result is hard to interpret due to differences in how animals were housed and assigned to specific experimental studies. While the causes of death were not different between SIV-infected and uninfected SMs that died before age 15 (i.e., adult), we found significant differences in the relative frequency of specific causes of death in the elderly population (≥15 years old). Specifically, we observed that SIV-infected SMs were more likely to die from infections but less likely to die from cardiovascular disease (and diabetes in female animals) as compared to uninfected SMs. While confirming the non-pathogenic nature of SIV infection in SMs, these data reveal, for the first time, a qualitative impact of SIV infection on the host physiology that induces a significant change in the mortality pattern in these natural SIV hosts., Importance: In this study, we demonstrate, for the first time, that the natural, non-pathogenic SIV infection of the African monkey SM has a clinical impact which is revealed in terms of main causes of mortality, which are significantly different in the infected animals as compared to the uninfected ones. Indeed, SIV-infected SMs are at higher risk of dying of infectious diseases but appear to be somewhat protected from cardiovascular causes of death. The identification of a specific pattern of mortality associated with the infection suggests that the host-pathogen interaction between SIV and the SM immune system, while non-pathogenic in nature, has a detectable impact on the overall health status of the animals., Competing Interests: The authors declare no conflict of interest.

The geographic origin of Plasmodium vivax, a leading cause of human malaria, has been the subject of much speculation. Here we review the evolutionary history of P. vivax and P. vivax-like parasites in humans and non-human primates on three continents, providing overwhelming evidence for an African origin. This conclusion is consistent with recent reports showing that Duffy-negative humans in Africa are, in fact, susceptible to P. vivax, with parasites invading Duffy-antigen-expressing erythroid precursors. Thus, the African origin of P. vivax not only explains the distribution of the Duffy-negative genotype but also provides new insight into the history and status of P. vivax malaria in Africa and efforts geared toward its eradication., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Broadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition., Highlights: Isolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaquesCryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognitionAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame twoThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodiesStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition modePropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naïve rhesus repertoireDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity.

HIV-1 evades antibody-dependent cellular cytotoxicity (ADCC) responses not only by controlling Env conformation and quantity at the cell surface but also by altering NK cell activation via the downmodulation of several ligands of activating and co-activating NK cell receptors. The signaling lymphocyte activation molecule (SLAM) family of receptors, which includes NTB-A and 2B4, act as co-activating receptors to sustain NK cell activation and cytotoxic responses. These receptors cooperate with CD16 (FcγRIII) and other activating receptors to trigger NK cell effector functions. In that context, Vpu-mediated downregulation of NTB-A on HIV-1-infected CD4 T cells was shown to prevent NK cell degranulation via an homophilic interaction, thus contributing to ADCC evasion. However, less is known on the capacity of HIV-1 to evade 2B4-mediated NK cell activation and ADCC. Here, we show that HIV-1 downregulates the ligand of 2B4, CD48, from the surface of infected cells in a Vpu-dependent manner. This activity is conserved among Vpu proteins from the HIV-1/SIVcpz lineage and depends on conserved residues located in its transmembrane domain and dual phosphoserine motif. We show that NTB-A and 2B4 stimulate CD16-mediated NK cell degranulation and contribute to ADCC responses directed to HIV-1-infected cells to the same extent. Our results suggest that HIV-1 has evolved to downmodulate the ligands of both SLAM receptors to evade ADCC. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) can contribute to the elimination of HIV-1-infected cells and HIV-1 reservoirs. An in-depth understanding of the mechanisms used by HIV-1 to evade ADCC might help develop novel approaches to reduce the viral reservoirs. Members of the signaling lymphocyte activation molecule (SLAM) family of receptors, such as NTB-A and 2B4, play a key role in stimulating NK cell effector functions, including ADCC. Here, we show that Vpu downmodulates CD48, the ligand of 2B4, and this contributes to protect HIV-1-infected cells from ADCC. Our results highlight the importance of the virus to prevent the triggering of the SLAM receptors to evade ADCC., Competing Interests: The authors declare no conflict of interest.

Reproductive inequality, or reproductive skew, drives natural selection, but has been difficult to assess, particularly for males in species with promiscuous mating and slow life histories, such as bonobos ( Pan paniscus ) and chimpanzees ( Pan troglodytes ). Although bonobos are often portrayed as more egalitarian than chimpanzees, genetic studies have found high male reproductive skew in bonobos. Here, we discuss mechanisms likely to affect male reproductive skew in Pan , then re-examine skew patterns using paternity data from published work and new data from the Kokolopori Bonobo Reserve, Democratic Republic of Congo and Gombe National Park, Tanzania. Using the multinomial index ( M ), we found considerable overlap in skew between the species, but the highest skew occurred among bonobos. Additionally, for two of three bonobo communities, but no chimpanzee communities, the highest ranking male had greater siring success than predicted by priority-of-access. Thus, an expanded dataset covering a broader demographic range confirms that bonobos have high male reproductive skew. Detailed comparison of data from Pan highlights that reproductive skew models should consider male-male dynamics including the effect of between-group competition on incentives for reproductive concessions, but also female grouping patterns and factors related to male-female dynamics including the expression of female choice. This article is part of the theme issue 'Evolutionary ecology of inequality'.

Host restriction factors play key roles in innate antiviral defense, but it remains poorly understood which of them restricts HIV-1 in vivo. Here, we used single-cell transcriptomic analysis to identify host factors associated with HIV-1 control during acute infection by correlating host gene expression with viral RNA abundance within individual cells. Wide sequencing of cells from one participant with the highest plasma viral load revealed that intracellular viral RNA transcription correlates inversely with expression of the gene PTMA , which encodes prothymosin α. This association was genome-wide significant ( P adjusted < 0.05) and was validated in 28 additional participants from Thailand and the Americas with HIV-1 CRF01&#95;AE and subtype B infections, respectively. Overexpression of prothymosin α in vitro confirmed that this cellular factor inhibits HIV-1 transcription and infectious virus production. Our results identify prothymosin α as a host factor that restricts HIV-1 infection in vivo, which has implications for viral transmission and cure strategies.

Ubiquitin is an extraordinarily highly conserved 76 amino acid protein encoded by three different types of gene, where the primary translation products are fusions either of ubiquitin with one of two ribosomal proteins (RPs) or of multiple ubiquitin monomers from head to tail. Here, we investigate the evolution of ubiquitin genes in mammalian malaria parasites (Plasmodium species). The ubiquitin encoded by the RPS27a fusion gene is highly divergent, as previously found in a variety of protists. However, we also find that two other forms of divergent ubiquitin sequence, each previously thought to be extremely rare, have arisen recently during the divergence of Plasmodium subgenera. On two occasions, in two distinct lineages, the ubiquitin encoded by the RPL40 fusion gene has rapidly diverged. In addition, in one of these lineages, the polyubiquitin genes have undergone a single codon insertion, previously considered a unique feature of Rhizaria. There has been disagreement whether the multiple ubiquitin coding repeats within a genome exhibit concerted evolution or undergo a birth-and-death process; the Plasmodium ubiquitin genes show clear signs of concerted evolution, including the spread of this codon insertion to multiple repeats within the polyubiquitin gene., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Populations on the edge of a species' distribution may represent an important source of adaptive diversity, yet these populations tend to be more fragmented and are more likely to be geographically isolated. Lack of genetic exchanges between such populations, due to barriers to animal movement, can not only compromise adaptive potential but also lead to the fixation of deleterious alleles. The south-eastern edge of chimpanzee distribution is particularly fragmented, and conflicting hypotheses have been proposed about population connectivity and viability. To address this uncertainty, we generated both mitochondrial and MiSeq-based microsatellite genotypes for 290 individuals ranging across western Tanzania. While shared mitochondrial haplotypes confirmed historical gene flow, our microsatellite analyses revealed two distinct clusters, suggesting two populations currently isolated from one another. However, we found evidence of high levels of gene flow maintained within each of these clusters, one of which covers an 18,000 km 2 ecosystem. Landscape genetic analyses confirmed the presence of barriers to gene flow with rivers and bare habitats highly restricting chimpanzee movement. Our study demonstrates how advances in sequencing technologies, combined with the development of landscape genetics approaches, can resolve ambiguities in the genetic history of critical populations and better inform conservation efforts of endangered species., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Background: Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction., Methods and Findings: We performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (β2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (<12 months), and intravenous immunoglobulin (IVIg) prophylaxis were all predictive of an inability to mount SARS-CoV-2 NAbs (all p ≤ 0.03). T cell response rates determined for a subset of participants were 2.8-fold lower for CLL patients compared to healthy controls (0.05, 95% CI 0.01 to 0.27, p < 0.001), with reduced intracellular IFNγ staining (p = 0.03) and effector polyfunctionality (p < 0.001) observed in CD4+ but not in CD8+ T cells. Surprisingly, in treatment-naïve CLL patients, BNT162b2 vaccination was identified as an independent negative risk factor for NAb generation (5.8, 95% CI 1.6 to 27, p = 0.006). CLL patients who received mRNA-1273 had 12-fold higher (p < 0.001) NAb titers and 1.7-fold higher (6.5, 95% CI 1.3 to 32, p = 0.02) response rates than BNT162b2 vaccinees despite similar disease characteristics. The absence of detectable NAbs in CLL patients was associated with reduced naïve CD4+ T cells (p = 0.03) and increased CD8+ effector memory T cells (p = 0.006). Limitations of the study were that not all participants were subjected to the same immune analyses and that pre-vaccination samples were not available., Conclusions: CLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naïve patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Qin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Humans and other primates harbour complex gut bacterial communities that influence health and disease, but the evolutionary histories of these symbioses remain unclear. This is partly due to limited information about the microbiota of ancestral primates. Here, using phylogenetic analyses of metagenome-assembled genomes (MAGs), we show that hundreds of gut bacterial clades diversified in parallel (that is, co-diversified) with primate species over millions of years, but that humans have experienced widespread losses of these ancestral symbionts. Analyses of 9,460 human and non-human primate MAGs, including newly generated MAGs from chimpanzees and bonobos, revealed significant co-diversification within ten gut bacterial phyla, including Firmicutes, Actinobacteriota and Bacteroidota. Strikingly, ~44% of the co-diversifying clades detected in African apes were absent from available metagenomic data from humans and ~54% were absent from industrialized human populations. In contrast, only ~3% of non-co-diversifying clades detected in African apes were absent from humans. Co-diversifying clades present in both humans and chimpanzees displayed consistent genomic signatures of natural selection between the two host species but differed in functional content from co-diversifying clades lost from humans, consistent with selection against certain functions. This study discovers host-species-specific bacterial symbionts that predate hominid diversification, many of which have undergone accelerated extinctions from human populations., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1 vaccine is challenging, including the extraordinary genetic diversity of HIV-1 and its complex mechanisms of immune evasion. HIV-1 envelope glycoproteins are poorly recognized by the immune system, which means that potent broadly neutralizing antibodies (bnAbs) are only infrequently induced in the setting of HIV-1 infection or through vaccination. Thus, the biology of HIV-1-host interactions necessitates novel strategies for vaccine development to be designed to activate and expand rare bnAb-producing B cell lineages and to select for the acquisition of critical improbable bnAb mutations. Here we discuss strategies for the induction of potent and broad HIV-1 bnAbs and outline the steps that may be necessary for ultimate success., (© 2022. Springer Nature Limited.)

HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these animals identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. IMPORTANCE An effective HIV-1 vaccination strategy will need to stimulate rare precursor B cells of multiple bNAb lineages and affinity mature them along desired pathways. Here, we searched for V2-apex germ line-targeting Envs among a large set of diverse primate lentiviruses and identified minimally modified versions of one chimpanzee SIV Env that bound several human V2-apex bNAb precursors and stimulated one of these in a V2-apex bNAb precursor-expressing knock-in mouse. We also generated chimeric simian-chimpanzee immunodeficiency viruses and showed that they elicit low-titer V2-directed heterologous plasma breadth in six of seven infected rhesus macaques. Characterization of this antibody response identified a new class of weakly cross-reactive neutralizing antibodies that target the V2-apex, but only in occluded-open Env trimers. The existence of this cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design.

The malaria parasite Plasmodium falciparum causes substantial human mortality, primarily in equatorial Africa. Enriched in affected African populations, the B*53 variant of HLA-B, a cell surface protein that presents peptide antigens to cytotoxic lymphocytes, confers protection against severe malaria. Gorilla, chimpanzee, and bonobo are humans' closest living relatives. These African apes have HLA-B orthologs and are infected by parasites in the same subgenus (Laverania) as P. falciparum, but the consequences of these infections are unclear. Laverania parasites infect bonobos (Pan paniscus) at only one (TL2) of many sites sampled across their range. TL2 spans the Lomami River and has genetically divergent subpopulations of bonobos on each side. Papa-B, the bonobo ortholog of HLA-B, includes variants having a B*53-like (B07) peptide-binding supertype profile. Here we show that B07 Papa-B occur at high frequency in TL2 bonobos and that malaria appears to have independently selected for different B07 alleles in the two subpopulations., (© 2023. The Author(s).)

Plasmodium falciparum malaria originated when Plasmodium praefalciparum , a gorilla malaria parasite transmitted by African sylvan anopheline mosquitoes, adapted to humans. Pfs47, a protein on the parasite surface mediates P. falciparum evasion of the mosquito immune system by interacting with a midgut receptor and is critical for Plasmodium adaptation to different anopheline species. Genetic analysis of 4,971 Pfs47 gene sequences from different continents revealed that Asia and Papua New Guinea harbor Pfs47 haplotypes more similar to its ortholog in P. praefalciparum at sites that determine vector compatibility, suggesting that ancestral P. falciparum readily adapted to Asian vectors. Consistent with this observation, Pfs47-receptor gene sequences from African sylvan malaria vectors, such as Anopheles moucheti and An. marshallii , were found to share greater similarity with those of Asian vectors than those of vectors of the African An. gambiae complex. Furthermore, experimental infections provide direct evidence that transformed P. falciparum parasites carrying Pfs47 orthologs of P. praefalciparum or P. reichenowi were more effective at evading the immune system of the Asian malaria vector An. dirus than An. gambiae . We propose that high compatibility of ancestral P. falciparum Pfs47 with the receptors of Asian vectors facilitated the early dispersal of human malaria to the Asian continent, without having to first adapt to sub-Saharan vectors of the An. gambiae complex.

The envelope glycoprotein (Env) is the main focus of human immunodeficiency virus type 1 (HIV-1) vaccine development due to its critical role in viral entry. Despite advances in protein engineering, many Env proteins remain recalcitrant to recombinant expression due to their inherent metastability, making biochemical and immunological experiments impractical or impossible. Here, we report a novel proline stabilization strategy to facilitate the production of prefusion Env trimers. This approach, termed "2P," works synergistically with previously described SOSIP mutations and dramatically increases the yield of recombinantly expressed Env ectodomains without altering the antigenic or conformational properties of near-native Env. We determined that the 2P mutations function by enhancing the durability of the prefusion conformation and that this stabilization strategy is broadly applicable to evolutionarily and antigenically diverse Env constructs. These findings provide a new Env stabilization platform to facilitate biochemical research and expand the number of Env variants that can be developed as future HIV-1 vaccine candidates. IMPORTANCE Recent estimates have placed the number of new human immunodeficiency virus type 1 (HIV-1) infections at approximately 1.5 million per year, emphasizing the ongoing and urgent need for an effective vaccine. The envelope (Env) glycoprotein is the main focus of HIV-1 vaccine development, but, due to its inherent metastability, many Env variants are difficult to recombinantly express in the relatively large quantities that are required for biochemical studies and animal trials. Here, we describe a novel structure-based stabilization strategy that works synergistically with previously described SOSIP mutations to increase the yield of prefusion HIV-1 Env.

HIV-1 envelope (Env) conformation determines the susceptibility of infected CD4 + T cells to antibody-dependent cellular cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more "open" conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu, and Env. Limited data exist, however, of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. While Nef, Vpu, and Env are all required to efficiently downregulate CD4 on infected CD4 + T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared with CD4 + T cells. However, treatment of infected macrophages with small CD4 mimetics exposes vulnerable CD4-induced Env epitopes and sensitizes them to ADCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)